A machine learning approach for predicting treatment response of hyponatremia.

Hyponatremia leads to severe central nervous system disorders and requires immediate treatment in some cases. However, a rapid increase in serum sodium (s-Na) concentration could cause osmotic demyelination syndrome. To achieve a safety hyponatremia treatment, we develop a prediction model of s-Na concentration using a machine learning. Among the 341 and 47 patients admitted to two tertiary hospitals for hyponatremia treatment (s-Na <130 mEq/L), those who were admitted to the general unit with urine sodium <20 mEq/L or treated with desmopressin were excluded. Ultimately, 74 and 15 patients (342 and 146 6-hourly datasets) were included in the learning and validation data, respectively. We trained the prediction model using three regression algorithms for shallow machine learning to predict s-Na every 6 h during treatment with the data of patients with hyponatremia (median s-Na: 112.5 mEq/L; range: 110.0-116.8 mEq/L) from one hospital. The model was validated externally using the data of patients with hyponatremia (median s-Na: 117.0 mEq/L; range: 112.9-120.0 mEq/L) from another hospital. Using 5-7 predictors (water intake, sodium intake, potassium intake, urine volume, s-Na concentration, serum potassium concentration, serum chloride concentration), the support vector regression model showed the best performance overall (root mean square error = 0.05396; R2 = 0.92), followed by the linear regression and regression tree models. The predicted s-Na levels, using explainable machine learning algorithms and clinically accessible parameters, correlated well with the actual levels. Thus, our model could be applied to the treatment of hyponatremia in clinical practice.

Effects of Digitization of Self-Monitoring of Blood Glucose Records Using a Mobile App and the Cloud System on Outpatient Management of Diabetes: Single-Armed Prospective Study.

BACKGROUND: In recent years, technologies promoting the digitization of self-monitoring of blood glucose (SMBG) records including app-cloud cooperation systems have emerged. Studies combining these technological interventions with support from remote health care professionals have reported improvements in glycemic control. OBJECTIVE: To assess the use of an app-cloud cooperation system linked with SMBG devices in clinical settings, we evaluated its effects on outpatient management of diabetes without remote health care professional support. METHODS: In this multicenter, open-label, and single-armed prospective study, 48 patients with diabetes (including type 1 and type 2) at 3 hospitals in Japan treated with insulin or glucagon-like peptide 1 receptor agonists and performing SMBG used the app-cloud cooperation system for 24 weeks. The SMBG data were automatically uploaded to the cloud via the app. The patients could check their data, and their attending physicians reviewed the data through the cloud prior to the patients' regular visits. The primary outcome was changes in glycated hemoglobin (HbA1c) levels. RESULTS: Although HbA1c levels did not significantly change in all patients, the frequency of daily SMBG following applying the system was significantly increased before induction at 12 (0.60 per day, 95% CI 0.19-1.00; P=.002) and 24 weeks (0.43 per day, 95% CI 0.02-0.84; P=.04). In the subset of 21 patients whose antidiabetic medication had not been adjusted during the intervention period, a decrease in HbA1c level was observed at 12 weeks (P=.02); however, this significant change disappeared at 24 weeks (P=.49). The Diabetes Treatment Satisfaction Questionnaire total score and "Q4: convenience" and "Q5: flexibility" scores significantly improved after using the system (all P<.05), and 72% (33/46) patients and 76% (35/46) physicians reported that the app-cloud cooperation system helped them adjust insulin doses. CONCLUSIONS: The digitization of SMBG records and sharing of the data by patients and attending physicians during face-to-face visits improved self-management in patients with diabetes. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCTs042190057; https://jrct.niph.go.jp/en-latest-detail/jRCTs042190057.

Response to endoplasmic reticulum stress in arginine vasopressin neurons.

Arginine vasopressin (AVP) is an antidiuretic hormone synthesized principally in the hypothalamic supraoptic and paraventricular nuclei. The immunoglobulin heavy chain binding protein (BiP), one of the most abundant endoplasmic reticulum (ER) chaperones, is highly expressed in AVP neurons, even under basal conditions. Moreover, its expression is upregulated in proportion to the increase in AVP expression under dehydration. These data suggest that AVP neurons are constantly exposed to ER stress. BiP knockdown in AVP neurons induces ER stress and autophagy, resulting in AVP neuronal loss, indicating that BiP is pivotal in maintaining the AVP neuron system. Furthermore, inhibition of autophagy after BiP knockdown exacerbates AVP neuronal loss, suggesting that autophagy induced under ER stress is a protective cellular mechanism by which AVP neurons cope with ER stress. Familial neurohypophysial diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the AVP gene. It is characterized by delayed-onset progressive polyuria and eventual AVP neuronal loss. In AVP neurons of FNDI model mice, mutant protein aggregates are confined to a specific compartment of the ER, called the ER-associated compartment (ERAC). The formation of ERACs contributes to maintaining the function of the remaining intact ER, and mutant protein aggregates in ERACs undergo autophagic-lysosomal degradation without isolation or translocation from the ER, representing a novel protein degradation system in the ER.

Possible Advantage of Glucagon-Like Peptide 1 Receptor Agonists for Kidney Transplant Recipients With Type 2 Diabetes.

CONTEXT: Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have the potential to improve native kidney function. OBJECTIVE: This work aimed to elucidate the possible protective effects of GLP-1 RAs on kidney graft function after successful kidney transplantation (KTX). METHODS: This retrospective cohort study included all KTX recipients (KTRs) at our facility with type 2 diabetes who were followed up from 1 month post-transplantation for 24 months or longer as of December 31, 2020. We investigated associations between the use of GLP-1 RAs and other antidiabetic medications (non-GLP-1 RAs) and the risk of sustained estimated glomerular filtration rate (eGFR) reduction (40% reduction compared with baseline for 4 months) for KTRs with type 2 diabetes. We calculated the propensity score of initiating GLP-1 RAs compared with that of initiating non-GLP-1 RAs as a function of baseline covariates using logistic regression. The inverse probability of the treatment-weighted odds ratio was estimated to control for baseline confounding variables. Sodium-glucose cotransporter 2 inhibitor use was a competing event. The primary outcome was sustained eGFR reduction of at least 40% from baseline for 4 months post-transplantation. RESULTS: Seventy-three patients were GLP-1 RA users and 73 were non-GLP-1 RA users. Six patients and 1 patient in the non-GLP-1 RA and GLP-1 RA groups had sustained eGFR reduction. GLP-1 RA use after KTX was associated with a lower risk of sustained eGFR reduction. CONCLUSION: GLP-1 RAs resulted in lower eGFR reduction compared with non-GLP-1 RAs and may contribute to better kidney graft survival after KTX.

Squamous cell carcinoma antigens are sensitive biomarkers for atopic dermatitis in children and adolescents: a cross-sectional study.

BACKGROUND: We recently reported that squamous cell carcinoma antigen 2 (SCCA2) is a reliable biomarker for atopic dermatitis (AD). OBJECTIVE: To further clarify its utility, we investigated for effects of comorbid allergies and AD treatment on serum SCCA levels. METHODS: Volunteers <18 years old were recruited through our website. Their allergic status was elucidated using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. We also recruited pediatric patients who were hospitalized because of severe AD. The serum levels of SCCA1 and SCCA2 were measured by enzyme-linked immunosorbent assays. In the severe AD patients, the levels of thymus and activation-regulated chemokine (TARC), SCCA1, and SCCA2 were measured before and after hospitalization. The severity of AD was assessed using the severity scoring of atopic dermatitis (SCORAD). RESULTS: A total of 576 participants (547 volunteers and 29 patients) were enrolled in the study. The levels of SCCA1 and SCCA2 were significantly higher in volunteers with mild AD and patients with severe AD than in healthy volunteers without allergic diseases. The levels were not elevated in those who had mild bronchial asthma or allergic rhinitis without AD. TARC, SCCA1, and SCCA2 were decreased during the treatment in severe AD patients, reflecting clinical improvement in response to treatment. Linear regression analysis for predicting a decrease in the SCORAD index showed R2 values of 0.16, 0.38, and 0.48 for TARC, SCCA1, and SCCA2, respectively. CONCLUSION: SCCAs, especially SCCA2, are sensitive biomarkers for detecting AD in children and adolescents and for assessing the severity and response to treatment of severe AD.

Pathological Roles and Clinical Usefulness of Periostin in Type 2 Inflammation and Pulmonary Fibrosis.

Periostin is known to be a useful biomarker for various diseases. In this article, we focus on allergic diseases and pulmonary fibrosis, for which we and others are now developing detection systems for periostin as a biomarker. Biomarker-based precision medicine in the management of type 2 inflammation and fibrotic diseases since heterogeneity is of utmost importance. Periostin expression is induced by type 2 cytokines (interleukin-4/-13) or transforming growth factor-ß, and plays a vital role in the pathogenesis of allergic inflammation or interstitial lung disease, respectively, andits serum levels are correlated disease severity, prognosis and responsiveness to the treatment. We first summarise the importance of type 2 biomarker and then describe the pathological role of periostin in the development and progression of type 2 allergic inflammation and pulmonary fibrosis. In addition, then, we summarise the recent development of assay methods for periostin detection, and analyse the diseases in which periostin concentration is elevated in serum and local biological fluids and its usefulness as a biomarker. Furthermore, we describe recent findings of periostin as a biomarker in the use of biologics or anti-fibrotic therapy. Finally, we describe the factors that influence the change in periostin concentration under the healthy conditions.

Arginine vasopressin-Venus reporter mice as a tool for studying magnocellular arginine vasopressin neurons.

Arginine vasopressin (AVP) synthesized in the magnocellular neurons of the hypothalamus is transported through their axons and released from the posterior pituitary into the systemic circulation to act as an antidiuretic hormone. AVP synthesis and release are precisely regulated by changes in plasma osmolality. Magnocellular AVP neurons receive innervation from osmosensory and sodium-sensing neurons, but previous studies showed that AVP neurons per se are osmosensitive as well. In the current study, we made AVP-Venus reporter mice and showed that Venus was expressed exclusively in AVP neurons and was upregulated under water deprivation. In hypothalamic organotypic cultures from the AVP-Venus mice, Venus-labeled AVP neurons in the supraoptic and paraventricular nuclei survived for 1 month, and Venus expression was upregulated by forskolin. Furthermore, in dissociated Venus-labeled magnocellular neurons, treatment with NaCl, but not with mannitol, decreased Venus fluorescence in the soma of the AVP neurons. Thus, Venus expression in AVP-Venus transgenic mice, as well as in primary cultures, faithfully showed the properties of intrinsic AVP expression. These findings indicate that AVP-Venus mice as well as the primary hypothalamic cultures could be useful for studying magnocellular AVP neurons.

Serum squamous cell carcinoma antigen (SCCA)-2 correlates with clinical severity of pediatric atopic dermatitis in Ishigaki cohort.

BACKGROUND: We sometimes encounter difficulties in assessing the severity of pediatric atopic dermatitis (AD) using currently available biomarkers such as thymus and activation-regulated chemokine (TARC) due to the higher baseline values in non-AD children. Recent case control studies have indicated the usefulness of squamous cell carcinoma antigens (SCCAs) in pediatric and adult AD. Notably, SCCAs are induced by IL-4 and IL-13, vital Th2 cytokines that play important roles in AD etiology. OBJECTIVES: Relatively low prevalence and mild disease severity of pediatric AD are observed in our Ishigaki cohort presumably due to the moisturising subtropical climate, which could conversely mean possible higher allergic potential of non-AD subjects towards AD. Thus, the purpose of this study was to further investigate the feasibility of using SCCAs together with TARC and periostin as biomarkers for pediatric AD even in the Ishigaki cohort. METHODS: We enrolled 1459 nursery school children and identified 96 as having AD through 2009-2011. As statistical analyses, we performed Student's t-test, correlation analysis, and receiver and operating characteristic (ROC) analysis. RESULTS: Serum SCCA1, SCCA2, periostin and TARC levels were all significantly increased in AD compared with those in non-AD, but only serum SCCA2 showed a significant increase in AD when assessed in each age group or in subgroup analysis. Among the biomarkers tested, serum SCCA2 also showed the best correlations with clinical AD severity and TARC and showed the best diagnosability for AD in ROC analysis. CONCLUSIONS: SCCA2 is a potent biomarker for pediatric AD in the Ishigaki cohort.

Chemical chaperone 4-phenylbutylate reduces mutant protein accumulation in the endoplasmic reticulum of arginine vasopressin neurons in a mouse model for familial neurohypophysial diabetes insipidus.

Familial neurohypophysial diabetes insipidus (FNDI), characterized by progressive polyuria and loss of arginine vasopressin (AVP) neurons, is an autosomal dominant disorder caused by AVP gene mutations. Our previous studies with FNDI model mice demonstrated that mutant proteins accumulated in the endoplasmic reticulum (ER) of AVP neurons. Here, we examined therapeutic effects of the chemical chaperone 4-phenylbutylate (4-PBA) in FNDI mice. Treatment with 4-PBA reduced mutant protein accumulation in the ER of FNDI mice and increased AVP release, leading to reduced urine volumes. Furthermore, AVP neuron loss under salt loading was attenuated by 4-PBA treatment. These data suggest that 4-PBA ameliorated mutant protein accumulation in the ER of AVP neurons and thereby prevented FNDI phenotype progression.

Squamous Cell Carcinoma Antigen 2 (SCCA2, SERPINB4): An Emerging Biomarker for Skin Inflammatory Diseases.

Squamous cell carcinoma antigens 1 and 2 (SCCA1 and 2, SERPIN B3 and B4), members of the ovalbumin serpin (ov-serpin)/clade B serpin family, were originally discovered as tumor-specific antigens and are used as tumor markers for various kinds of squamous cell carcinomas. Recently, our understanding of the underlying mechanisms of how SCCA1/2 enhance tumor growth has greatly increased. Moreover, it has been shown that SCCA1/2 are involved in the pathogenesis of several inflammatory diseases: asthma, psoriasis, and atopic dermatitis (AD). IL-22 and IL-17, signature cytokines of type 17 inflammation, as well as IL-4 and IL-13, signature cytokines of type 2 inflammation, both of which are positively correlated with the pathogenesis of psoriasis and allergic diseases, respectively, can induce expression of SCCA1/2 in airway epithelial cells and/or keratinocytes, leading to high expression of SCCA1/2 in these diseases. Based on these findings, several trials have been performed to examine the potential of applying SCCA1/2 to biomarkers for these diseases. The findings show that SCCA2 is useful to aid diagnosis, estimate clinical severity and disease type, and assess responses to treatment in psoriasis and AD. These results suggest that SCCA2 has emerged as a novel biomarker for skin inflammatory diseases.

Up-regulation of serum periostin and squamous cell carcinoma antigen levels in infants with acute bronchitis due to respiratory syncytial virus.

BACKGROUND: Periostin and squamous cell carcinoma antigen (SCCA) are involved in the pathogenesis of asthma. Acute bronchitis due to respiratory syncytial virus (RSV) infection during infancy exhibits an asthma-like pathogenesis, suggesting that it may be associated with the subsequent development of asthma. However, the mechanism by which RSV infection leads to development of asthma has not yet been fully elucidated. METHODS: Infants younger than 36 months were enrolled and classified into three groups. Group I included patients hospitalized with RSV-induced bronchitis. These patients were further stratified into two sub-groups according to whether the criteria for the modified Asthma Predictive Index (mAPI) had been met: Group I consisted of mAPI (+) and mAPI (-) patients; Group II included patients with food allergy as a positive control group; and Group III included children with no allergy as a negative control group. Serum periostin and SCCA levels were measured in the groups. This study was registered as a clinical trial (UMIN000012339). RESULTS: We enrolled 14 subjects in Group I mAPI (+), 22 in Group I mAPI (-), 18 in Group II, and 18 in Group III. In Group I, the serum periostin and SCCA levels were significantly higher during the acute phase compared with the recovery phase. However, no significant differences were found between Group I mAPI (+) and mAPI (-). CONCLUSIONS: The serum periostin and SCCA levels increased during acute RSV bronchitis. Both periostin and SCCA may play a role in the pathogenesis of acute bronchitis due to RSV.

Serum levels of squamous cell carcinoma antigens 1 and 2 reflect disease severity and clinical type of atopic dermatitis in adult patients.

BACKGROUND: Recent studies have indicated that serum levels of squamous cell carcinoma antigen (SCCA) 1 and 2 induced by type 2 cytokines such as IL-4 and IL-13, are increased in patients with atopic dermatitis (AD). However, no clinical studies have analyzed serum levels of SCCA2 in larger series of AD patients or their association with various clinical characteristics. This study was performed to clarify whether serum levels of SCCA2 are associated with disease severity and clinical phenotypes of adult AD patients. METHODS: An enzyme-linked immunosorbent assay was performed to examine serum SCCA2 levels in 240 adult patients with AD and 25 healthy controls in this study. Serum SCCA2 levels were analyzed with clinical characteristics and laboratory parameters including thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), blood eosinophils, total IgE, and specific IgE (Japanese cedar pollen, Dermatophagoides farina, Candida, malassezia, Staphylococcal enterotoxin B). Expression of SCCA2 in AD eruption was examined by immunohistochemistry. The effect of treatment on serum SCCA2 was also assessed. RESULTS: Serum SCCA2 level showed a positive correlation with disease severity, levels of TARC, LDH, eosinophil counts, and IgE levels. Robust expression of SCCA2 was detected in the supra basal keratinocytes in the epidermis of AD patients. Serial measurements of serum SCCA2 revealed decreased levels of SCCA2 after treatment for AD. CONCLUSIONS: Serum SCCA2 levels reflected disease severity and clinical type of AD. Serum SCCA2 may thus be a relevant biomarker for AD.

Serum Biomarkers for the Diagnosis of Eosinophilic Esophagitis and Eosinophilic Gastroenteritis.

Objective Clinically useful serum biomarkers for the diagnosis and monitoring of eosinophilic gastrointestinal diseases are not available. This study was conducted to examine the possible value of eosinophil-related proteins as serum biomarkers. Methods The serum concentrations of 49 cytokines, chemokines, and other proteins were measured in 29 patients with eosinophilic gastrointestinal diseases and 80 controls. Results The levels of interleukin (IL)-5, IL-33, eotaxin-3, and thymic stromal lymphopoietin (TSLP), previously reported as possible biomarkers of eosinophilic esophagitis, were not significantly elevated in the serum. In contrast, the B cell-attracting chemokine (BCA)-1/chemokine (C-X-C motif) ligand (CXCL) 13 and hemofiltrate C-C chemokine (HCC)-1/CC chemokine ligand (CCL) 14α levels were significantly elevated, while the granulocyte chemotactic protein (GCP)-2/CXCL6 levels were suppressed in patients with eosinophilic esophagitis as well as in those with eosinophilic gastroenteritis. The cutaneus T cell-attracting chemokine (CTACK)/CCL27, stromal cell-derived factor (SDF)-1/CXCL12, macrophage inflammatory protein (MIP)-3ß/CCL19, and squamous cell carcinoma antigen (SCCA) 2 levels were elevated only in patients with eosinophilic esophagitis. However, there were large overlaps of data obtained from the patient and control groups, indicating that these serum biomarkers are not adequately sensitive for clinical use with presently available assay systems. Conclusion Of the 49 investigated serum proteins, none were shown to be adequately sensitive for use as biomarkers for the diagnosis or monitoring of eosinophilic gastrointestinal diseases.

The usefulness of monomeric periostin as a biomarker for idiopathic pulmonary fibrosis.

The natural course of idiopathic pulmonary fibrosis (IPF) is variable. Predicting disease progression and survival in IPF is important for treatment. We previously demonstrated that serum periostin has the potential to be a prognostic biomarker for IPF. Our aim was to use monomeric periostin in a multicenter study to evaluate its efficacy in diagnosing IPF and predicting its progression. To do so, we developed a new periostin kit to detect only monomeric periostin. The subjects consisted of 60 IPF patients in a multicenter cohort study. We applied monomeric periostin, total periostin detected by a conventional kit, and the conventional biomarkers-KL-6, SP-D, and LDH-to diagnose IPF and to predict its short-term progression as estimated by short-term changes of %VC and % DL, CO. Moreover, we compared the fraction ratios of monomeric periostin to total periostin in IPF with those in other periostin-high diseases: atopic dermatitis, systemic scleroderma, and asthma. Monomeric periostin showed the greatest ability to identify IPF comparable with KL-6 and SP-D. Both monomeric and total periostin were well correlated with the decline of %VC and % DL, CO. Clustering of IPF patients into high and low periostin groups proved useful for predicting the short-term progression of IPF. Moreover, the relative ratio of monomeric periostin was higher in IPF than in other periostin-high diseases. Measuring monomeric periostin is useful for diagnosing IPF and predicting its short-term progression. Moreover, the ratio of monomeric periostin to total periostin is elevated in IPF compared to other periostin-high diseases.

Central diabetes insipidus.

Central diabetes insipidus (CDI), characterized by polyuria and polydipsia, is caused by deficiency of arginine vasopressin (AVP), an antidiuretic hormone which acts on V2 receptors in kidney to promote reabsorption of free water. CDI is classified into three subtypes; idiopathic, secondary and familial. A previous study suggests that infundibulo-neurohypophysitis might be an underlying cause of idiopathic CDI. Among secondary CDI, the tumors in the central nervous system such as craniopharyngioma and germ cell tumors are the most frequent causes. Familial CDI is inherited mostly in an autosomal dominant mode, and the number of causal mutations in the AVP gene locus reported so far exceeds 80. CDI is treated with desmopressin, an analogue of vasopressin, and the tablet is preferred to the nasal form because it is easier to administer. It is also shown that the oral disintegrating tablet formula increases QOL and decreases the incidence of hyponatremia in CDI patients. In some CDI patients, the osmoreceptors in the hypothalamus do not function and patients do not sense thirst. These adipsic CDI patients are treated with desmopressin and adjusting the amount of daily water intake based on body weight measurement; but controlling the water balance is extremely difficult, and morbidity and mortality are shown to be high in these patients.

AgRP Neuron-Specific Deletion of Glucocorticoid Receptor Leads to Increased Energy Expenditure and Decreased Body Weight in Female Mice on a High-Fat Diet.

Agouti-related protein (AgRP) expressed in the arcuate nucleus is a potent orexigenic neuropeptide, which increases food intake and reduces energy expenditure resulting in increases in body weight (BW). Glucocorticoids, key hormones that regulate energy balance, have been shown in rodents to regulate the expression of AgRP. In this study, we generated AgRP-specific glucocorticoid receptor (GR)-deficient (knockout [KO]) mice. Female and male KO mice on a high-fat diet (HFD) showed decreases in BW at the age of 6 weeks compared with wild-type mice, and the differences remained significant until 16 weeks old. The degree of resistance to diet-induced obesity was more robust in female than in male mice. On a chow diet, the female KO mice showed slightly but significantly attenuated weight gain compared with wild-type mice after 11 weeks, whereas there were no significant differences in BW in males between genotypes. Visceral fat pad mass was significantly decreased in female KO mice on HFD, whereas there were no significant differences in lean body mass between genotypes. Although food intake was similar between genotypes, oxygen consumption was significantly increased in female KO mice on HFD. In addition, the uncoupling protein-1 expression in the brown adipose tissues was increased in KO mice. These data demonstrate that the absence of GR signaling in AgRP neurons resulted in increases in energy expenditure accompanied by decreases in adiposity in mice fed HFD, indicating that GR signaling in AgRP neurons suppresses energy expenditure under HFD conditions.

Unfolded protein response in hypothalamic cultures of wild-type and ATF6α-knockout mice.

Recent studies suggest that endoplasmic reticulum (ER) stress in the hypothalamus could affect systemic homeostatic regulation in areas such as energy and water balance. Activating transcription factor 6α (ATF6α) is an ER stress transducer which increases the expression of ER chaperones and ER-associated degradation (ERAD) components under ER stress. In the present study, we examined the regulation of the unfolding protein response (UPR) in mouse hypothalamic cultures of wild-type (WT) and ATF6α(-/-) mice. Thapsigargin (TG), an ER stressor, significantly increased the mRNA expression of immunoglobulin heavy chain binding protein (BiP), spliced X-box binding protein 1 (XBP1), activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), and ERAD components, in hypothalamic cultures of WT mice with the same threshold (0.1µM) and similar time courses. On the other hand, TG-induced upregulation of BiP and CHOP as well as most ERAD-related genes, but not spliced XBP1 or ATF4, was attenuated in ATF6α(-/-) mice compared with WT mice. Our data suggest that all the UPR arms are activated similarly in the mouse hypothalamus under ER stress conditions, where ATF6α regulates the expression of ER chaperones, CHOP, and ERAD components.

Activating transcription factor 6α is required for the vasopressin neuron system to maintain water balance under dehydration in male mice.

Activating transcription factor 6α (ATF6α) is a sensor of endoplasmic reticulum (ER) stress and increases the expression of ER chaperones and molecules related to the ER-associated degradation of unfolded/misfolded proteins. In this study, we used ATF6α knockout (ATF6α(-/-)) mice to clarify the role of ATF6α in the arginine vasopressin (AVP) neuron system. Although urine volumes were not different between ATF6α(-/-) and wild-type (ATF6α(+/+)) mice with access to water ad libitum, they were increased in ATF6α(-/-) mice compared with those in ATF6α(+/+) mice under intermittent water deprivation (WD) and accompanied by less urine AVP in ATF6α(-/-) mice. The mRNA expression of immunoglobulin heavy chain binding protein, an ER chaperone, was significantly increased in the supraoptic nucleus in ATF6α(+/+) but not ATF6α(-/-) mice after WD. Electron microscopic analyses demonstrated that the ER lumen of AVP neurons was more dilated in ATF6α(-/-) mice than in ATF6α(+/+) mice after WD. ATF6α(-/-) mice that were mated with mice possessing a mutation causing familial neurohypophysial diabetes insipidus (FNDI), which is characterized by progressive polyuria and AVP neuronal loss due to the accumulation of mutant AVP precursor in the ER, manifested increased urine volume under intermittent WD. The aggregate formation in the ER of AVP neurons was further impaired in FNDI/ATF6α(-/-) mice compared with that in FNDI mice, and AVP neuronal loss was accelerated in FNDI/ATF6α(-/-) mice under WD. These data suggest that ATF6α is required for the AVP neuron system to maintain water balance under dehydration.

The usefulness of combined measurements of squamous cell carcinoma antigens 1 and 2 in diagnosing atopic dermatitis.

BACKGROUND: The squamous cell carcinoma antigen (SCCA) is widely used as a serological biomarker for various cancers. There are two known SCCA molecules, SCCA1 and SCCA2. We previously found that interleukin-4 or interleukin-13, two related Th2-type cytokines that play an important role in allergic diseases, induce expression of SCCA1 and SCCA2. In this study, we examined whether combined measurements of SCCA1 and SCCA2 are useful for diagnosing atopic dermatitis (AD). METHODS: We established new enzyme-linked immunosorbent assays (ELISAs) to specifically detect SCCA1 or SCCA2. We applied serum samples from AD patients with food allergies and from cervical cancer patients to these ELISAs. We performed receiver operating characteristic analyses to diagnose AD and to distinguish AD from cervical cancer. RESULTS: Serum concentrations of both SCCA1 and SCCA2 were elevated in AD patients. The serum concentrations of SCCA1 and SCCA2 positively correlated with the clinical severity of AD, showing high specificity (0.86-0.88) and sensitivity (0.86) against control donors. The serum concentrations of SCCA1 and SCCA2 were elevated in cervical cancer patients; however, the SCCA2/SCCA1 ratios clearly distinguished AD patients from cervical cancer patients with high specificity (0.87) and sensitivity (0.87). Expression of SCCA2 was predominant in AD patients, whereas cervical cancer patients showed a predominance of SCCA1. CONCLUSIONS: Combined measurements of SCCA1 and SCCA2 are very useful in estimating the severity of allergic diseases, making it possible to distinguish allergic diseases from cancers.